US10363249B2 - Fatty acid synthase inhibitor for use in the treatment of drug resistant cancer - Google Patents

Fatty acid synthase inhibitor for use in the treatment of drug resistant cancer Download PDF

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US10363249B2
US10363249B2 US15/503,809 US201515503809A US10363249B2 US 10363249 B2 US10363249 B2 US 10363249B2 US 201515503809 A US201515503809 A US 201515503809A US 10363249 B2 US10363249 B2 US 10363249B2
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cancer
taxane
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Timothy Sean Heuer
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Sagimet Biosciences Inc
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3V Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates generally to modulators of lipid synthesis, e.g., fatty acid synthase inhibitors, and methods of use thereof.
  • the present modulators of lipid synthesis can be used for the treatment of paclitaxel-resistant cancers.
  • the present modulators of lipid synthesis can also be used to increase the sensitivity of a cancer to treatment with paclitaxel or Nab-paclitaxel.
  • the dominant therapeutic approaches that are currently employed to treat cancer include surgical removal of primary tumors, tumor irradiation, and parenteral application of anti-mitotic cytotoxic agents.
  • the continued dominance of long established therapies is mirrored by the lack of improvement in survival rates for most cancers.
  • Surgical intervention often results in a release of tumor cells into the circulation or lymph systems from which metastatic tumors can subsequently be established.
  • Paclitaxel is an anti-mitotic cytotoxic agent that has provided improvement in patient outcomes. Unfortunately, despite this success, many patients will eventually progress to a phase of the disease that becomes resistant or unresponsive to treatment with paclitaxel and other traditional chemotherapeutic drugs.
  • the compounds useful in the present invention have been disclosed as inhibitors of fatty acid synthesis in U.S. Publication No. 2012/0264737, International PCT Publication No. WO 2015/105860, and International PCT Publication No. WO 2014/008197, which are incorporated herein by reference in their entirety. Surprisingly, the compounds of the present disclosure have been found to be useful to resensitize paclitaxel-resistant cancers to treatment with paclitaxel or Nab-paclitaxel.
  • the present invention is directed to fatty acid synthase inhibitors and methods of use thereof.
  • Fatty acid synthase inhibitors can be used for the treatment of paclitaxel-resistant cancers.
  • Fatty acid synthase inhibitors can also be used to increase the sensitivity of a cancer to taxanes such as paclitaxel, Nab-paclitaxel, docetaxel, and cabazitaxel.
  • the methods and compositions described herein are useful for treating a paclitaxel-resistant tumor or cancer in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a fatty acid synthase inhibitor and a therapeutically effective amount of paclitaxel or Nab-paclitaxel.
  • a method for treating a paclitaxel-resistant cancer in a subject comprising:
  • the methods and compositions described herein are useful for treating or preventing a tumor or cancer in a subject in need thereof, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a fatty acid synthase inhibitor and a therapeutically effective amount of paclitaxel or Nab-paclitaxel.
  • the methods and compositions described herein are useful for enhancing the activity of paclitaxel or Nab-paclitaxel in treating a tumor or a cancer, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a fatty acid synthase inhibitor and a therapeutically effective amount of paclitaxel or Nab-paclitaxel.
  • the methods and compositions described herein are useful for increasing the sensitivity of a tumor or cancer cell to paclitaxel or Nab-paclitaxel, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a fatty acid synthase inhibitor and a therapeutically effective amount of paclitaxel or Nab-paclitaxel.
  • the fatty acid synthase inhibitor described herein is a compound having the structure of:
  • R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein: C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
  • R 3 is H, —OH, or halogen
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
  • t is 0 or 1;
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • L 1 is CR 23 or N
  • L 2 is CR 23 or N
  • L 1 or L 2 is N;
  • R 23 is H or C 1 -C 4 straight or branched alkyl.
  • compositions which comprise:
  • R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein: C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, —OH, or halogen
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 24 is independently, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
  • t is 0 or 1;
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • L 1 is CR 2 or N
  • L 2 is CH or N
  • L 1 or L 2 is N;
  • R 23 is H or C 1 -C 4 straight or branched alkyl
  • the fatty acid synthase inhibitor is one or more compounds, forms, and/or agents that act as an inhibitor of FASN gene expression or FASN protein activity.
  • the fatty acid synthase inhibitor can be selected from cerulenin, 4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid (C75), orlistat, C93 (FAS93), FAS31, C247, GSK837149A ((4,4′-(carbonylbis(azanediyl))bis(N-(4-methylpyrimidin-2-yl)benzenesulfonamide)), platensimycin, ( ⁇ )-epigallocatechin-3-gallate (EGCG), luteolin, taxifolin, kaempferol, quercetin, apigenin, catchin, soy protein, and oleic acid, or the like.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms (C 1-12 alkyl), preferably one to eight carbon atoms (C 1 -C 8 alkyl) or one to six carbon atoms (C 1 -C 6 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethy
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted.
  • Alkoxy refers to a radical of the formula —OR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.
  • Alkylamino refers to a radical of the formula —NHR a or —NR a R a where each R a is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted.
  • Thioalkyl refers to a radical of the formula —SR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.
  • “Aralkyl” refers to a radical of the formula —R b —R c where R b is an alkylene chain as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.
  • “Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.
  • Cycloalkylalkyl refers to a radical of the formula —R b R d where R d is an alkylene chain as defined above and R g is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.
  • fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • Heterocyclyl or “heterocyclic ring” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group may be optionally substituted.
  • Heterocyclylalkyl refers to a radical of the formula —R b R e where R b is an alkylene chain as defined above and R e is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group may be optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula —R b R f where R b is an alkylene chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.
  • substituted means any of the above groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g., a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • substituted includes any of the above groups in which one or more hydrogen atoms are replaced with —NR g R h , —NR g C( ⁇ O)R h , —NR g C( ⁇ O)NR g R h , —NR g C( ⁇ O)OR h , —NR g SO 2 R h , —OC( ⁇ O)NR g R h , —OR g , —SR g , —SOR g , —SO 2 R g , —OSO 2 R g , —SO 2 OR g , ⁇ NSO 2 R g , and —SO 2 NR g R h .
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with —C( ⁇ O)R g , —C( ⁇ O)OR g , —C( ⁇ O)NR g R h , —CH 2 SO 2 R g , —CH 2 SO 2 NR g R h , —(CH 2 CH 2 O) 2-10 R g .
  • R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group.
  • the above non-hydrogen groups are generally referred to herein as “substituents”.
  • each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see. Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).
  • prodrugs are provided in Higuchi, T., et al., A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a subject for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • an animal such as rat, mouse, guinea pig, monkey, or to human
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Subject or “patient” includes mammals, which includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that are associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and formulations of the present invention.
  • Optional or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • Effective amount refers to that amount of a compound of the invention which, when administered to a subject, preferably a human, is sufficient to treat a paclitaxel-resistant cancer, or to re-sensitize a paclitaxel-resistant cancer to treatment with paclitaxel or Nab-paclitaxel.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age or weight of the subject to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a subject, preferably a human, having the disease or condition of interest, and includes:
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and ( ⁇ ), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present invention includes tautomers of any said compounds.
  • “Paclitaxel” refers to paclitaxel and all various form or derivatives thereof, e.g., nanoparticle albumin-bound paclitaxel (“Nab-paclitaxel”).
  • “Paclitaxel-resistant” refers to a tumor, a cancerous cell, or a patient diagnosed with cancer that has intrinsic or acquired resistance to the chemotherapeutic effect of paclitaxel. This includes, without limitation, tumors or cancers that were once responsive to paclitaxel but have become refractory or unresponsive to treatment with paclitaxel.
  • Docetaxel-resistant refers to a tumor, a cancerous cell, or a patient diagnosed with cancer that has intrinsic or acquired resistance to the chemotherapeutic effect of docetaxel. This includes, without limitation, tumors or cancers that were once responsive to docetaxel but have become refractory or unresponsive to treatment with paclitaxel.
  • “Cabazitaxel-resistant” refers to a tumor, a cancerous cell, or a patient diagnosed with cancer that has intrinsic or acquired resistance to the chemotherapeutic effect of cabazitaxel. This includes, without limitation, tumors or cancers that were once responsive to cabazitaxel but have become refractory or unresponsive to treatment with cabazitaxel.
  • Tumor-resistant refers to a tumor, a cancerous cell, or a patient diagnosed with cancer that has intrinsic or acquired resistance to the chemotherapeutic effect of a taxane. This includes, without limitation, tumors or cancers that were once responsive to a taxane but have become refractory or unresponsive to treatment with taxane.
  • a compound of the invention, or pharmaceutically acceptable derivatives thereof may be administered simultaneously with, prior to, or after administration of any other compound of the invention.
  • Compounds of the invention, or pharmaceutically acceptable derivatives thereof may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents.
  • Such combination therapies include administration of a single pharmaceutical dosage formulation which contains one or more compounds of the invention, as well as administration of one compound of the invention and another compound of the invention in their own separate pharmaceutical dosage formulation.
  • the compounds of the invention can be administered to the patient together in a single dosage formulation such as a tablet, capsule or injection, or each agent administered in separate dosage formulations.
  • the compounds of the invention may be administered to the patient via any of the accepted modes of administration of agents for serving similar utilities.
  • the compounds of the invention (and as applicable, any additional active agents) can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially.
  • Combination therapy is understood to include all these treatment regimens.
  • the additional therapeutically active agent included in a pharmaceutical combination or treatment regime of the invention is selected, for example, from paclitaxel and Nab-paclitaxel.
  • compositions which comprise:
  • R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein: C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, —OH, or halogen
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
  • t is 0 or 1;
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • L 1 is CR 23 or N
  • L 2 is CH or N
  • L 1 or L 2 is N;
  • R 23 is H or C 1 -C 4 straight or branched alkyl
  • R 24 is C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein t is 0 or 1.
  • R 21 is halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom, —S(O) u —(C 1 -C 4 straight or branched alkyl) wherein u is 0 or 2, or —S(O) u —(C 3 -C 5 cycloalkyl) wherein u is 0 or 2;
  • R 3 is H or halogen.
  • R 1 is halogen, —CN or C 1 -C 2 haloalkyl.
  • both L 1 and L 2 are N.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 24 is —(C 1 -C 2 alkyl) t -O—(C 1 -C 2 alkyl) wherein t is 0 or 1.
  • R 21 is C 3 -C 5 cycloalkyl
  • R 22 is C 1 -C 2 alkyl
  • R 24 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl
  • R 22 is C 1 -C 2 alkyl
  • R 24 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl
  • R 3 is H or F.
  • R 1 is —CN.
  • R 1 is —CF 3 .
  • R 22 is H, methyl or ethyl.
  • R 22 is H.
  • R 22 is methyl
  • R 1 is —CN
  • each R 2 is hydrogen
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • L 1 and L 2 are N
  • R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.
  • R 1 is —CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • L 1 and L 2 are N
  • R 24 is methoxy or ethoxy.
  • R 1 is —CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • L 1 is CH
  • L 2 is N
  • R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
  • R 1 is —CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • L 1 is N
  • L 2 is CH
  • R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • compositions which comprise: (i) a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), or (XXIX), or a pharmaceutically acceptable salt thereof, and (ii) a taxane.
  • compositions which comprise: (i) a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), or (XXIX), or a pharmaceutically acceptable salt thereof, and (ii) paclitaxel.
  • compositions which comprise: (i) a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), or (XXIX), or a pharmaceutically acceptable salt thereof, and (ii) Nab-paclitaxel.
  • compositions which comprise: (i) a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), or (XXIX), or a pharmaceutically acceptable salt thereof, and (ii) docetaxel.
  • compositions which comprise: (i) a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XIX), (XX), (XXIII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), or (XXIX), or a pharmaceutically acceptable salt thereof, and (ii) cabazitaxel.
  • fatty acid synthase inhibitors can also be used to increase the sensitivity of a cancer to taxanes such as paclitaxel, Nab-paclitaxel, docetaxel, and cabazitaxel.
  • the methods and compositions described herein are useful for treating a taxane-resistant tumor or cancer in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a fatty acid synthase inhibitor and a therapeutically effective amount of a taxane.
  • One aspect of the present invention relates to a method of treating or preventing a taxane-resistant tumor or cancer in a subject in need thereof, the method comprising administering to the subject a fatty acid synthase inhibitor compound having the structure of:
  • R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein: the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, —OH, or halogen
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:
  • t is 0 or 1;
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • L 1 is CR 23 or N
  • X, Y, and Z are each independently CR or NR′, wherein R is hydrogen or C 1-6 alkyl and R′ is hydrogen, C 1-6 alkyl, or absent;
  • A is CH or N
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond
  • n 1 or 2;
  • n 0 or 1
  • X, Y, and Z are each independently CR or NR′, wherein R is hydrogen or C 1-6 alkyl and R′ is hydrogen, C 1-6 alkyl, or absent;
  • L and D are each independently C or N;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl, heterocyclyl, —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , ⁇ —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond
  • n 1 or 2;
  • n 0 or 1
  • X, Y, and Z are each independently CR or NR′, wherein R is hydrogen or C 1-6 alkyl and R′ is hydrogen, C 1-6 alkyl, or absent;
  • Q is C or N
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or if Q is N then R 3 is absent;
  • R 4 is hydrogen, heteroaryl, heterocyclyl, —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond
  • R 19 is aryl, heteroaryl, cycloalkyl, or heterocyclyl
  • n 0, 1, or 2;
  • n 0 or 1
  • L 1 , L 2 , L 3 , L 4 , and A are each independently CH or N;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 )C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 23 is hydrogen, —N(R 13 )(R 14 ), C 1-6 alkyl, C 1-6 alkoxy, is absent if L 1 is N, or R 23 and R 24 taken together with the atoms to which they are attached join together to form a heterocyclyl, heteroaryl, or cycloalkyl;
  • R 24 is hydrogen, —N(R 13 )(R 14 ), C 1-6 alkyl, C 1-6 alkoxy, —(C 1-6 alkoxy)(heterocyclyl), heterocyclyl, or R 23 and R 24 taken together with the atoms to which they are attached join together to form a heterocyclyl, heteroaryl, or cycloalkyl;
  • R 26 is hydrogen, heteroaryl, heterocyclyl, —N(R 13 )(R 14 ), or —S( ⁇ O) 2 R 20 ;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 25 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • L 7 is N or O, wherein R 30 is absent if L 7 is O;
  • A is CH or N
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 29 and R 30 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, —N(R 15 R 16 ), —C( ⁇ O)R 46 , —R 48 C( ⁇ O)R 47 , or R 29 and R 30 taken together with the atoms to which they are attached join together to form a heteroaryl or heterocyclyl, wherein R 30 is absent if L 7 is O;
  • R 46 and R 47 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 48 is alkyl or is absent
  • R 31 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • v 0 or 1
  • L 13 , L 14 , L 15 , and A are each independently CH or N;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 34 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or —N(R 15 R 16 );
  • R 35 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 36 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —N(R 15 R 16 ), heterocyclyl, or heteroaryl;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy.
  • R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein: the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, —OH, or halogen
  • R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 35 is —C(O)—R 351 , —C(O)—NHR 351 , —C(O)—O—R 351 or S(O) 2 R 351 ;
  • R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • L 16 is C or N, wherein R 41 is absent if L 16 is N.
  • L 17 , L 18 , and A are each independently CH or N;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 40 , R 42 , and R 43 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , —C( ⁇ O)R, hydroxyalkyl, hydroxyl, —N(R 13 R 14 ), or R 41 and R 42 taken together with the atoms to which they are attached join together to form a heteroaryl or heterocyclyl;
  • R 41 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , —C( ⁇ O)R, hydroxyalkyl, hydroxyl, —N(R 13 R 14 ), R 41 is absent if L 16 is N, or R 41 and R 42 taken together with the atoms to which they are attached join together to form a heteroaryl or heterocyclyl;
  • R is hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 39 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • L 19 and A are each independently CH or N;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 . —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 39 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 44 and R 45 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, —S( ⁇ O) 2 R 20 , —C( ⁇ O)R, or —N(R 13 R 14 ); and
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein: the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, —OH or halogen
  • L 3 is C(R 60 ) 2 , O or NR 50 ;
  • each R 60 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 wherein:
  • t 0 or 1
  • each R 50 is independently H, —C(O)—O t —(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 501 ) 2 , C 1 -C 4 straight or branched alkyl wherein:
  • t is 0 or 1
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • n 1, 2 or 3;
  • n 1 or 2;
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • R 22 is H, halogen, C 1 -C 2 alkyl
  • each R 26 is independently —OH, —CN, halogen, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 1 -C 4 alkyl), or —C(O)—N(R 501 ) 2 wherein:
  • t 0 or 1
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • s 0, 1 or 2;
  • each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl
  • two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 ;
  • R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • R 1 when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, —OH, or halogen
  • R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl
  • R 22 is H, halogen, C 1 -C 2 alkyl
  • R 351 is C 1 -C 2 alkyl or C 2 —O—(C 1 or C 2 alkyl);
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen. R 1 is optionally substituted with one or more halogen;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
  • R 22 is H, halogen or C 1 -C 2 alkyl
  • R 24 is —O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O—(C 3 -C 5 cycloalkyl), or —O-(4- to 6-membered heterocycle), wherein R 24 is optionally substituted with one or more hydroxyl or halogen; and
  • R 25 is H, halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, wherein R 25 is optionally substituted with one or more halogen;
  • L 3 is —CH 2 —, —CHR 50 —, —O—, —NR 50 —, —NC(O)R 50 — or —NC(O)OR 50 —, wherein R 50 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;
  • n 1, 2, or 3;
  • n 1 or 2 wherein n+m ⁇ 3;
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl) t -N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O t -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
  • each t is independently 0 or 1;
  • each R 241 is independently H or C 1 -C 2 alkyl
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
  • t is 0 or 1;
  • u is 0 or 1
  • each R 241 is independently H or C 1 -C 2 alkyl
  • R 25 is halogen. —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl or cyclopropyl;
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
  • R 22 is H, halogen or C 1 -C 2 alkyl
  • each R 24 and R 25 is independently H, halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , O—(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:
  • each t is independently 0 or 1;
  • each u is independently 0 or 1;
  • each R 241 is independently H or C 1 -C 2 alkyl
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;
  • R 3 is H or F;
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
  • R 22 is H, halogen or C 1 -C 2 alkyl; and each of R 24 and R 25 is independently H, —C 1 -C 4 alkyl,
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
  • R 22 is H, halogen or C 1 -C 2 alkyl
  • R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:
  • R 241 is H or C 1 -C 2 alkyl.
  • L 2 is —NHR 35 or —C(O)NHR 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl) wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 35 is —C(O)R 351 , —C(O)NHR 351 , C(O)OR 351 or S(O) 2 R 351 wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl,
  • each W, X, Y and Z is independently —N— or —CR 26 — with the proviso that not more than 2 of W, X, Y and Z are —N—;
  • each R 26 is independently H, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 27 ) 2 , —S(O) 2 —(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkyl);
  • each R 27 is independently H or C 1 -C 4 alkyl or both R 27 are C 1 -C 4 alkyl and join to form a 3- to 6-membered ring together with the N to which they are attached and wherein the ring optionally includes one oxygen atom as one of the members of the ring;
  • Het is a 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl) wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle;
  • R 22 is H, halogen or C 1 -C 2 alkyl.
  • R 3 is F.
  • A is CH.
  • A is N.
  • X, Y, and Z are NR′.
  • R 4 is heteroaryl, heterocyclyl, —C( ⁇ O)N(R 5 R 6 ),
  • R 5 is hydrogen and R 6 is aryl or heteroaryl.
  • the compound is of the Formula (IV-A) or (IV-B):
  • X, Y, and Z are each independently CR or NR′, wherein R is hydrogen or C 1-6 alkyl and R′ is hydrogen, C 1-6 alkyl, or absent;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), (CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond.
  • the compound is of the Formula (IV-C) or (IV-D):
  • X, Y, and Z are each independently CR or NR′, wherein R is hydrogen or C 1-6 alkyl and R′ is hydrogen, C 1-6 alkyl, or absent; R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (IV-E), (IV-F), (IV-G), (IV-H):
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (IV-I), (IV-J), or (IV-K):
  • X and Y are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), (CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (IV-L) or (IV-M):
  • X and Y are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (IV-N) or (IV-O):
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (IV-Q), (IV-R), or (IV-S):
  • X, Y, and Z are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S(O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (IV-V):
  • X, Y, and Z are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —CF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of one the following Formula (IV-X), (IV-Y), (IV-Z), (IV-AA), (IV-AB, (IV-AC), (IV-AD), (IV-AF), (IV-AG), or (IV-AH):
  • X, Y, and Z are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-4 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • X and Y are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (V-C), (V-D), or (V-E):
  • X and Y are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ) and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (VI-A), (VI-B), or (VI-C):
  • X and Y are each independently CR or NR′, wherein R is H or C 1-6 alkyl and R′ is H, C 1-6 alkyl, or absent;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 4 is hydrogen, heteroaryl
  • heterocyclyl —C( ⁇ O)N(R 5 R 6 ), —N(R 7 )C( ⁇ O)R 8 , —N(R 9 R 10 ), C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —N(R 13 R 14 ), CF 3 , —OCF 3 , —S( ⁇ O) 2 R 20 , or R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or —N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compound is of the Formula (VI-D), (VI-E), or (VI-F):
  • the compound is of the Formula (VII-A) or (VII-B):
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 26 is hydrogen, heteroaryl, heterocyclyl, —N(R 13 )(R 14 ), or —S( ⁇ O) 2 R 20 ;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 25 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.
  • the compound is of the Formula (VII-C) or (VII-D):
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 25 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1 -6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • s 0, 1, or 2;
  • L 5 is CH 2 , NH, S, or O;
  • L 6 is CH or N
  • R 27 is hydrogen, —C( ⁇ O)R′′, —S( ⁇ O) 2 R 20 ;
  • R 28 is hydrogen, —C( ⁇ O)R′′, —S( ⁇ O) 2 R 20 , or is absent if L 6 is O;
  • R′′ is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), or —N(R 13 )(R 14 ).
  • R 1 is hydrogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, or —C( ⁇ O)N(R 13 )(R 14 ).
  • R 1 is cyano
  • R 2 is hydrogen or halo; R 2 is hydrogen.
  • R 3 is hydrogen
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 25 is hydrogen
  • L 2 is N.
  • L 1 is CH.
  • L 3 is CH.
  • L 4 is CH.
  • A is N.
  • A is CH.
  • R 26 is heterocyclyl
  • R 24 is —N(R 13 )(R 14 ).
  • L 5 and L 6 are each independently N.
  • s is 1.
  • the compound is of the Formula (X-A), (X-B), (X-C), or (X-D):
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 30 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, —N(R 15 R 16 ), —C( ⁇ O)R 46 , or —R 48 C( ⁇ O)R 47 , wherein R 30 is absent if L 7 is O;
  • R 46 and R 47 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 48 is alkyl or is absent
  • R 31 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • L 8 , L 9 , and L 10 are each independently CH 2 , NH, or O;
  • L 11 and L 12 are each independently CH or N;
  • R 32 and R 33 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —S( ⁇ O) 2 R 20 , —C( ⁇ O)R 46 , hydroxyalkyl, hydroxyl, or are absent;
  • u 0, 1, or 2;
  • t 0, 1, or 2.
  • L 7 is N.
  • L 7 is O.
  • A is N.
  • A is CH.
  • R 1 is hydrogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, or —C( ⁇ O)N(R 13 )(R 14 ).
  • R 1 is cyano
  • R 2 is hydrogen or halo.
  • R 2 is hydrogen
  • R 3 is fluorine
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 31 is hydrogen
  • R 30 is hydrogen
  • L 8 is O.
  • L 9 is O.
  • L 10 is O and L 11 is N.
  • L 12 is N.
  • R 32 and R 33 are each independently hydrogen.
  • the compound is of Formula (X-I), (X-J), (X-K), (X-L), (X-M), (X-N), or (X-O):
  • the compound is of the Formula (XI-C) or (XI-D):
  • R 1 is hydrogen, cyano, halo, C 1-6 alkyl, C 1-6 alkoxy, —C( ⁇ O)N(R 13 )(R 14 ), —(CH 2 ) q C( ⁇ O)N(R 13 )(R 14 ), CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or —N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 21 and R 22 are each independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, CF 3 , —OCF 3 , or —S( ⁇ O) 2 R 20 ;
  • R 35 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 36 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —N(R 15 R 16 ), heterocyclyl, or heteroaryl;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, —N(R 15 R 16 ), or —S( ⁇ O) 2 R 20 ;
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • R 37 and R 38 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, or R 37 and R 38 taken together with the atoms to which they are attached join together to form a heteroaryl or heterocyclyl.
  • R 1 is hydrogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, or —C( ⁇ O)N(R 13 )(R 14 ).
  • R 1 is cyano
  • R 2 is hydrogen or halo.
  • R 2 is hydrogen
  • R 3 is fluorine.
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 35 is hydrogen
  • R 34 is heteroaryl.
  • R 34 is thienyl, pyrrole, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl, or benzothiadiazolyl
  • L 13 is N.
  • L 14 and L 15 are each independently CH.
  • A is N.
  • A is CH.
  • the compound is of the Formula (XI-E), (XI-F), (XI-G), (XI-H), or (XI-I):
  • R 3 is H or halogen.
  • R 1 is halogen, —CN or C 1 -C 2 haloalkyl.
  • R 22 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl
  • R 3 is H or F.
  • R 1 is —CN.
  • R 1 is —CF 3 .
  • R 22 is H, methyl or ethyl.
  • R 22 is H.
  • R 22 is methyl
  • R 35 is —C(O)—NHR 351 .
  • R 351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl
  • R 351 is (R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.
  • R 1 is —CN
  • each R 2 is hydrogen
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is H
  • R 22 is —C(O)—NHR 351 where R 351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
  • R 35 is —C(O)—O—R 351 .
  • R 351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
  • R 1 is —CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is H
  • R 35 is —C(O)—O—R 351 where R 351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
  • R 351 is (R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.
  • compounds have a structure selected from the group consisting of:
  • R 1 is hydrogen, cyano C 1-6 alkyl, C 1-6 alkoxy, or
  • R 1 is cyano
  • R 2 is hydrogen or halo.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 39 is hydrogen.
  • R 40 is hydrogen
  • L 16 is N.
  • L 17 is N.
  • L 18 is CH.
  • L 18 is N.
  • A is N.
  • A is CH.
  • R 42 is C 1-6 alkyl.
  • R 41 is C 1-6 alkyl.
  • the compound is of the Formula (XIV-C) or (XIV-D):
  • R 1 is hydrogen, cyano. C 1-6 alkyl, C 1-6 alkoxy, or —C( ⁇ O)NN(R 13 )(R 14 ).
  • R 1 is cyano.
  • R 2 is hydrogen or halo.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 39 is hydrogen.
  • L 19 is N.
  • A is N.
  • A is CH.
  • R 21 is halogen, C 1 -C 4 straight or branched alkyl or C 3 -C 5 cycloalkyl.
  • R 3 is H or halogen.
  • R 1 is —CN or C 1 -C 2 haloalkyl.
  • R 3 is H or F.
  • R 1 is —CN.
  • R 1 is —CF 3 .
  • n 1
  • n is 2.
  • m is 1.
  • m is 2.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • n is 2
  • m is 1
  • L 3 is —N—C(O)—O—(C 1 -C 2 alkyl).
  • L 3 is NR 50 ;
  • R 50 is C 1 -C 2 alkyl;
  • R 21 is cyclobutyl;
  • R 22 is H or methyl;
  • R 3 is H;
  • R 1 is —CN;
  • m is 2 and n is 1 or 2.
  • n is 2
  • m is 1
  • L 3 is O and s is 0.
  • R 22 is H, methyl or ethyl.
  • R 22 is methyl
  • R 22 is H.
  • R 1 is —CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • n is 2
  • L 3 is NR 50 where R 50 is methyl or ethyl.
  • R 1 is —CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • n is 2 and L 3 is O.
  • the compound has a structure selected from the group consisting of:
  • R 3 is H or halogen.
  • R 1 is halogen, —CN or C 1 -C 2 haloalkyl.
  • R 21 is C 3 -C 4 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl
  • R 3 is H or F.
  • R 1 is —CN.
  • R 1 is —CF 3 .
  • R 22 is H, methyl or ethyl.
  • R 22 is H.
  • R 22 is methyl
  • R 1 is —CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is cyclobutyl
  • R 22 is methyl
  • R 351 is methyl or ethyl.
  • the compound has a structure selected from the group consisting of:
  • L-Ar is
  • L-Ar is
  • L-Ar is
  • R 3 is H.
  • R 1 is —CN or —O—(C 1 -C 4 alkyl), wherein when R 1 is not —CN, R 1 is optionally substituted with one or more halogen.
  • R 1 is —CN.
  • R 1 is —O—(C 1 -C 4 alkyl) optionally substituted with one or more halogen.
  • R 2 is hydrogen
  • R 21 is C 1 -C 4 alkyl.
  • R 22 is H or C 1 -C 2 alkyl.
  • R 24 is —O—(C 1 -C 4 alkyl) optionally substituted with one or more hydroxyl or halogen.
  • R 24 is —O—(C 1 -C 4 alkyl) optionally substituted with one or more hydroxyl.
  • R 25 is —CH 3 .
  • the compound has a structure selected from the group consisting of:
  • L-Ar is
  • L-Ar is
  • R 1 is H, —CN, —C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl) wherein when R 1 is not H or —CN, R 1 is optionally substituted with one or more halogens.
  • R 1 is halogen, —CN or C 1 -C 2 haloalkyl.
  • R 1 is —CN or C 1 -C 2 haloalkyl.
  • R 1 is —CN.
  • R 1 is —Cl.
  • R 2 is H.
  • R 21 is halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl.
  • R 21 is C 3 -C 5 cycloalkyl.
  • R 22 is H or C 1 -C 2 alkyl.
  • R 22 is H.
  • R 22 is C 1 -C 2 alkyl.
  • R 22 is —CH 3 .
  • L 3 is —N(CH 3 )—.
  • n 2 and m is 2.
  • n 1 or 2.
  • n 1 and m is 2.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is H or C 1 -C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is H or C 1 -C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is H or —CH 3 .
  • Het is an optionally substituted 5- to 6-membered heteroaryl
  • R 1 is H, —CN, halogen, optionally substituted C 1 -C 4 alkyl, —O-(optionally substituted C 3 -C 5 cycloalkyl), —O-(optionally substituted 4- to 6-membered heterocycle) or —O-(optionally substituted C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen.
  • R 1 is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or optionally substituted C 1 -C 4 alkyl
  • R 3 is H or F
  • R 11 is H or —CH 3 ;
  • R 21 is H, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 5 cycloalkyl or optionally substituted 4- to 6-membered heterocycle:
  • R 22 is H, halogen or optionally substituted C 1 -C 2 alkyl
  • R 24 is H, optionally substituted C 1 -C 4 alkyl, -(optionally substituted C 1 -C 4 alkyl)-OH, -(optionally substituted C 1 -C 4 alkyl)-N(R 241 ) 2 , -(optionally substituted C 1 -C 4 alkyl) t -O t -(optionally substituted C 3 -C 5 cycloalkyl), -(optionally substituted C 1 -C 4 alkyl) t -O t -(optionally substituted 4- to 6-membered heterocycle) or -(optionally substituted C 1 -C 4 alkyl) t -O-(optionally substituted C 1 -C 4 alkyl), wherein:
  • t is 0 or 1
  • R 241 is H or optionally substituted C 1 -C 2 alkyl.
  • L-Ar is

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US11622968B2 (en) 2011-03-08 2023-04-11 Sagimet Biosciences Inc. Heterocyclic modulators of lipid synthesis
US11034690B2 (en) 2016-11-11 2021-06-15 Saginiet Biosciences Inc. Heterocyclic modulators of lipid synthesis

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